PROJECT SUMMARY/ABSTRACT Ovarian clear cell carcinoma (OCCC) is an aggressive subtype of epithelial ovarian cancer with very poor prognosis when diagnosed in advanced stage. Although typically treated like other invasive epithelial ovarian cancers with cytoreductive surgery and platinum/taxanes, OCCC shows only ~15% clinical response rate to chemotherapy, highlighting the critical need for new treatment approaches. OCCC progresses through shedding, survival, and accumulation of tumor cells in malignant ascites, resulting in the seeding of metastases throughout the peritoneal cavity; this ongoing process of metastasis is a major contributor to morbidity and mortality. We seek therapies targeting pathways critical for tumor cell attachment-free survival so as to sensitize OCCC cells to apoptosis, to benefit patients even in the setting of advanced-stage disease. In previous work we have identified serine protease inhibitor Kazal type 1 (SPINK1) as an independent marker of ovarian cancer poor prognosis that promotes attachment-free cell survival and proliferation in experimental models. In preliminary data using OCCC cell lines, we find that SPINK1 is regulated by autocrine interleukin-6 (IL-6) signaling. We hypothesize that IL-6 induces SPINK1 expression resulting in anoikis resistance, proliferation, and progression of OCCC, and that pharmacological inhibition of IL-6 signaling pathways can suppress SPINK1 expression and offer therapeutic benefit in OCCC. Our specific aims are designed to test this hypothesis and to lay a foundation for clinical trials for translation of our discoveries into effective new therapies for OCCC. (1) We will define the IL-6/SPINK1 axis regulating cell survival and proliferation in OCCC, using established cell-based models of OCCC. (2) We will evaluate pharmacological inhibition of IL-6 signaling as a therapeutic strategy for intervention in IL-6/SPINK1-driven cell survival, proliferation, cancer progression and metastasis, using established OCCC cell lines and patient-derived tumor xenograft (PDX) models. (3) We will evaluate the prognostic value of IL-6 and SPINK1 tumor tissue expression in an OCCC cohort, identifying strategies for biomarker-based stratification of OCCC patients for IL-6-targeted treatment. Together our proposed studies will define a novel approach for therapeutic intervention in OCCC progression and identify the patients best able to benefit.